Ondansetron (1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one) and its polymorph (ondansetron hydrochloride dihydrate) are selective inhibitors of the serotonin 5-HT3 receptor type, and are marketed for the treatment of nausea under the tradenames ZOFRAN ODT® and ZOFRAN®, respectively (GlaxoSmithKline, Research Triangle Park, N.C.).
A number of synthetic pathways for ondansetron have been reported, which involve the use of undesirable reactants or require multiple steps and undue length of time. WO 02/055492 A2 (the '492 application) discloses a process of using 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one as an initial substrate to prepare dimethylamino-methyl carbazolone, which is then converted to ondansetron. The '492 application process involves the use of dimethylamine, a chemical weapons precursor, as a reactant, and glacial acetic acid, a corrosive solvent, in a reaction that requires heating for 12 hours. U.S. Pat. No. 4,695,578 (the '578 patent) discloses a process of reacting 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with a source of formaldehyde and dimethylamine to prepare 3-[(dimethylamino)methyl]-1,2,39-tetrahydro-9-methyl-4H-carbazole-4-one hydrochloride, which is then converted via multiple steps to form ondansetron. Because dimethylamine is a precursor to the nerve agent Tabun, it is a controlled substance in many countries.
Kim et al. (Heterocycles 1997, 45, 2041) disclose a two-step synthesis of ondansetron. In the first step of the synthesis, 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (compound of formula 1, Scheme 1) is reacted with a source of formaldehyde and morpholine in boiling glacial acetic acid to provide 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one (compound of formula 2, Scheme 1). In the second step of the synthesis, 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one is reacted with 2-methylimidazole in the presence of alumina (Al2O3) to provide ondansetron (See, Scheme 1).

In the first step of the Kim et al. synthesis, an α-methylene group is added to 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one in a Mannich-related reaction. The success of the Mannich-related reaction appears to depend on the structure of the ketone substrate. Kim et al. explicitly state that reactants that are successful in other Mannich-related reactions are unsatisfactory for 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one. For example, formaldehyde/NaOH (used in complex tetralone derivatives; Wagh, A. P. et al., Ind. J. Chem., 1974, 12, 923); trioxane/N-methylanilinium trifluoroacetate in tetrahydrofuran or dioxane (used in cyclic ketones; Gras, J-L, Tetrahedron Lett., 1978, 2111); and formaldehyde/diethylamine (used in thiorphan analogs; Thierry, M. et al., Bioorg. Med. Chem. Lett., 1992, 2, 949) are not suitable to add an α-methylene group to 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one.
In the second step of the Kim et al. synthesis, ondansetron is prepared by conjugate (Michael) addition of 2-methyl-imidazole to the exocyclic methylene group of 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one. Pelletier et al. (Tetrahedron Lett. 1980, 21, 809) explicitly state that this type of reaction generally does not occur, or takes place in low yield after a long reaction time in the absence of alumina. U.S. Pat. No. 4,695,578 discloses that when applied to the synthesis of ondansetron, the reaction in the absence of alumina takes place in low yield after a long reaction time (i.e., 43%, 20 hours).
The two-step synthesis of ondansetron disclosed by Kim et al. also suffers several major disadvantages. First, glacial acetic acid is combustible, caustic, corrosive, and extremely destructive to the tissue of mucous membranes and upper respiratory tracts. Second, glacial acetic acid is heated to its boiling point (≧115° C.), a temperature far exceeding its flash point (40° C.). Third, morpholine is flammable, corrosive, and toxic. It is readily absorbed through human skin, and is harmful by inhalation, skin contact, and ingestion. Fourth, the 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one is isolated after the first step by removing the glacial acetic acid and morpholine under vacuum, which is time-consuming and expensive. Fifth, alumina adds to the expense of the process. Sixth, the alumina contaminates the isolated ondansetron, and thus must be removed by extracting the mixture with chloroform, which is a halogenated solvent, and is undesirable commercially.
A need exists for: i) a process for preparing 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one from 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one without employing glacial acetic acid as a solvent or a secondary amine (e.g., dimethylamine or morpholine) as a catalyst; and ii) a process for preparing ondansetron from the 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one without employing alumina as a catalyst.